1. Field of the Invention
This invention relates to novel compounds useful as contrast agents for magnetic resonance imaging, and in other diagnostic and therapeutic applications.
2. Description of the Prior Art
There are a variety of imaging techniques that have been used to diagnose disease in humans. One of the first imaging techniques employed was X-rays. In X-rays, the images produced of the patients' body reflect the different densities of body structures. To improve the diagnostic utility of this imaging technique, contrast agents are employed to increase the density between various structures, such as between the gastrointestinal tract and its surrounding tissues. Barium and iodinated contrast media, for example, are used extensively for X-ray gastrointestinal studies to visualize the esophagus, stomach, intestines and rectum. Likewise, these contrast agents are used for X-ray computed tomographic studies to improve visualization of the gastrointestinal tract and to provide, for example, a contrast between the tract and the structures adjacent to it, such as the vessels or lymph nodes. Such gastrointestinal contrast agents permit one to increase the density inside the esophagus, stomach, intestines and rectum, and allow differentiation of the gastrointestinal system from surrounding structures.
Magnetic resonance imaging (MRI) is a relatively new imaging technique which, unlike X-rays, does not utilize ionizing radiation. Like computed tomography, MRI can make cross-sectional images of the body, however MRI has the additional advantage of being able to make images in any scan plane (i.e., axial, coronal, sagittal or orthogonal). Unfortunately, the full utility of MRI as a diagnostic modality for the body, particularly in the abdominal and pelvic region, is hampered by the lack of an effective gastrointestinal contrast agent. Without such an agent, it is often difficult using MRI to differentiate the intestines from, for example, adjacent soft tissues and lymph nodes. If better contrast agents were available, the overall usefulness of MRI as an imaging agent would improve, and the diagnostic accuracy of this modality in the gastrointestinal region would be greatly enhanced.
MRI employs a magnetic field, radiofrequency energy and magnetic field gradients to make images of the body. The contrast or signal intensity differences between tissues mainly reflect the T1 and T2 relaxation values and the proton density (effectively, the free water content) of the tissues. In changing the signal intensity in a region of a patient by the use of a contrast medium, several possible approaches are available. For example, a contrast medium could be designed to change either the T1, the T2 or the proton density.
A paramagnetic contrast agent such as Gd-DTPA causes longitudinal relaxation to shorten T1. This increases the signal intensity on T1-weighted images. A superparamagnetic contrast agent such as ferrites works predominantly on transverse relaxation causing a shortening of T2 and decreasing signal intensity on T2-weighted images. A contrast agent could also work by altering the proton density, specifically by decreasing the amount of free water available that gives rise to the signal intensity.
Agents that increase the signal intensity from the lumen compared to the native contents are termed positive contrast agents. A number of these have been examined as contrast agents for MRI. These include fats and oils (Newhouse et al., Radiology, 142(P):246 (1982)), which increase signal as a result of their short T1, long T2 and high intrinsic proton density, as well as various paramagnetic agents that increase signal by decreasing the T1 of water protons. Examples of such paramagnetic agents include Gd-DTPA (Kornmesser et al., Magn. Reson. Imaging, 6:124 (1988), and Laniado et al., AJR, 150:817 (1988)), Gd-DOTA (Hahn et al. Magn. Reson. Imaging, 6:78 (1988)), Gd-oxalate (Runge, V. M. et al., Radiology, 147:789 (1983)), Cr-EDTA (Runge, V. M. et al., Physiol. Chem. Phys. Med. NMR, 16:113 (1984)), Cr-Tris-acetylacetonate (Clanton et al., Radiology, 149:238 (1983)), ferric chloride (Young et al., CT, 5:543 (1981)), ferrous gluconate (Clanton et al., Radiology, 153:159 (1984)), ferric ammonium citrate and ferrous sulfate (Wesbey et al., Radiology, 149:175 (1983) and Tscholakoff et al., AJR, 148:703 (1987)) as well as iron complexes (Wesbey et al., Magn. Reson. Imaging, 3:57 (1985), and Williams et al.,Radiology, 161:315 (1986)). Other paramagnetic contrast agents include saccharides or reduced lower carbohydrates bound to a compound coordinated with a paramagnetic ion (Gibby, U.S. Pat. Nos. 4,933,441, and 4,822,594), and liposomes entrapping paramagnetic ions (U.K. Patent Application GB 2193095).
Alternatively, agents that decrease the signal intensity from the lumen are termed negative contrast agents. Examples include particulate iron oxides (Hahn et al., Radiology, 164:37 (1987), Widder et al., AJR, 149:839 (1987)) which decrease signal via T2 shortening, as well as gas-evolving materials (Weinreb et al., J. Comput. Assist. Tomogr., 8:835 (1984)) and perfluorocarbons (Mattrey et al., AJR, 148:1259 (1987)) which act through changes in the proton density. It should be recognized that all paramagnetic substances at sufficiently high concentrations can also result in a decrease in signal intensity via T2 shortening.
The existing MRI contrast agents all suffer from a number of limitations, including problems with stability, degradation, relaxivity, signal intensity, biodistribution, toxicity, antigenicity and/or cost. For example, liposomes containing paramagnetic ions have the disadvantage that the lipid may oxidize in storage and, furthermore, the lipid itself may be quite expensive to employ. With saccharides or reduced lower carbohydrates bound to a compound coordinated to a paramagnetic ion, stability is a problem, and decomplexation and unfavorable biodistribution of the paramagnetic ion results.
New and/or better contrast agents useful in magnetic resonance imaging are needed. The present invention is directed to this, as well as other, important ends.